Transdermal delivery of cannabinoids

ABSTRACT

The present invention overcomes the problems associated with existing drug delivery systems by delivering cannabinoids transdermally. Preferably, the cannabinoids are delivered via an occlusive body (i.e., a patch) to alleviate harmful side effects and avoid gastrointestinal (first-pass) metabolism of the drug by the patient. A first aspect of the invention provides a method for relieving symptoms associated with illness or associated with the treatment of illness in a mammalian subject, comprising the steps of selecting at least one cannabinoid from the group consisting of cannabinol, cannabidiol, nabilone, levonantradol, (−)-HU-210, (+)-HU-210, 11-hydroxy-Δ 9 -THC, Δ 8 -THC-11-oic acid, CP 55,940, and R(+)-WIN 55,212-2, selecting at least one permeation enhancer from the group consisting of propylene glycol monolaurate, diethylene glycol monoethyl ether, an oleoyl macrogolglyceride, a caprylocaproyl macrogolglyceride, and an oleyl alcohol, and delivering the selected cannabinoid and permeation enhancer transdermally to treat an illness.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending U.S. patent applicationSer. No. 11/157,034, filed Jun. 20, 2005, which was acontinuation-in-part application of U.S. patent application Ser. No.10/032,163, filed Dec. 21, 2001, which claims priority to U.S.Provisional Patent Application No. 60/257,557, filed Dec. 22, 2000, eachof which is hereby incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention generally relates to the transdermal delivery ofcannabinoids. More particularly, the present invention relates to amethod and mode of transdermally delivering cannabinoids to treatvarious illnesses and/or symptoms.

2. Background Art

The use of cannabinoids to treat medical illnesses is of great interestto the medical community. Specifically, illnesses such as AIDS andcancer are often accompanied with a lack of appetite. Moreover, patientsreceiving cancer chemotherapy often experience nausea and vomiting sideeffects. Chronic pain (especially neuropathic pain), malignant tumors,spasticity (in multiple sclerosis and spinal cord injury), and ordystonia are additional therapeutic targets for cannabinoid therapy. Thecapability to control or eliminate these problems would greatly increasethe quality of life for many patients.

Heretofore, attempts have been made at administering the cannabinoidΔ⁹-THC (Dronabinol) orally, in the form of a capsule. However, severelynauseated patients are often not able to retain the capsule in theirstomachs long enough for the drug to take effect. This problem iscompounded by the fact that four to six doses of the capsule must betaken around chemotherapy. Another issue with capsules, as well assmoked marijuana, is that patients absorb the drug relatively rapidly(as compared to controlled drug delivery rates that a patch produces)and receive high drug concentrations in their body. These high drugconcentrations, or peak levels, are often associated with seriouspsychoactive and other central nervous system side effects.

In view of the above, there is a long felt need in the art for Δ⁹-THCand other cannabinoids to be delivered transdermally (across the skin).Preferably, such cannabinoids will be delivered by patch, bandage,topical formulation or the like and release the appropriate dose ofcannabinoids over time. There is also a need to transdermally delivercannabinoids other than Δ⁹-THC and Δ⁸-THC to treat various illnessesand/or symptoms.

SUMMARY OF THE INVENTION

The present invention overcomes the problems associated with existingdrug delivery systems by delivering cannabinoids transdermally.Preferably, the cannabinoids are delivered via an occlusive body (i.e.,a patch) to alleviate harmful side effects and avoid gastrointestinal(first-pass) metabolism of the drug by the patient.

A first aspect of the invention provides a method for relieving symptomsassociated with illness or associated with the treatment of illness in amammalian subject, comprising the steps of selecting at least onecannabinoid from the group consisting of cannabinol, cannabidiol,nabilone, levonantradol, (−)-HU-210, (+)-HU-210, 11-hydroxy-Δ⁹-THC,Δ⁸-THC-11-oic acid, CP 55,940, and R(+)-WIN 55,212-2, selecting at leastone permeation enhancer from the group consisting of propylene glycolmonolaurate, diethylene glycol monoethyl ether, an oleoylmacrogolglyceride, a caprylocaproyl macrogolglyceride, and an oleylalcohol, and delivering the selected cannabinoid and permeation enhancertransdermally to treat an illness.

A second aspect of the invention provides an occlusive body for thedelivery of cannabinoids, comprising an impermeable backing, arate-controlling microporous membrane, said backing and membranedefining a cavity therebetween, a cannabinoid disposed within thecavity, a permeation enhancer disposed within the cavity, and a viscousflowable gel confined between the backing and the membrane within thecavity for immobilizing the cannabinoid and the permeation enhancer.

A third aspect of the invention provides a method for increasing theconcentration of cannabinoids or cannabinoid metabolites in a subject,comprising contacting the subject's skin with a compound selected fromthe group consisting of cannabinol, cannabidiol, nabilone,levonantradol, (−)-HU-210, (+)-HU-210, 11-hydroxy-Δ⁹-THC, Δ⁸-THC-11-oicacid, CP 55,940, and R(+)-WIN 55,212-2 and contacting the subject's skinwith a permeation enhancer selected from the group consisting ofpropylene glycol monolaurate, diethylene glycol monoethyl ether, anoleoyl macrogolglyceride, a caprylocaproyl macrogolglyceride, and anoleyl alcohol.

The preferred embodiment of the present invention is designed to solvethe problems herein described and other problems not discussed, whichare discoverable by a skilled artisan.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of an occlusive body in accordance withthe present invention.

FIG. 2 is a permeation profile of showing the delivery of a cannabinoidacross skin.

FIG. 3 is a bar graph showing permeability of skin samples to acannabinoid for various receiver solutions.

FIG. 4 is a bar graph showing permeability of skin samples to acannabinoid for various receiver solutions.

FIG. 5A is a bar graph and FIG. 5B is a permeation profile, each showingpermeability of skin samples to a cannabinoid for various receiversolutions.

FIG. 6 is a bar graph showing permeability of skin samples to acannabinoid for various receiver solutions.

FIG. 7 is a bar graph showing permeability of stripped and intact skinsamples to a cannabinoid for various receiver solutions.

FIG. 8 is a bar graph showing maximum flux of a cannabinoid through skinsamples for various receiver solutions.

FIG. 9 is a permeation profile showing the delivery of cannabidiol usingpermeation enhancers.

FIG. 10 is a second permeation profile showing the delivery ofcannabidiol using permeation enhancers.

FIG. 11 is a graph of THC plasma concentrations following theadministration of THC alone and in combination with cannabidiol.

FIG. 12 is a graph of cannabidiol plasma concentrations following theadministration of cannabidiol alone and in combination with THC.

DETAILED DESCRIPTION

The present invention relates to a method for relieving symptomsassociated with illness or discomfort associated with the treatment ofillness in a subject.

Subjects who can benefit from the method of the present inventioninclude, for example, mammals, such as humans, particularly humansrequiring relief from chronic pain, such as neuropathic pain.

The method of the present invention can be used to relieve the symptomsof a variety of diseases, conditions, syndromes, disorders, and otherforms of illness. For example, as explained above, patients sufferingfrom illnesses, such as cancer and AIDS, often experience symptoms, suchas lack of appetite, which can be relieved with the method of thepresent invention. Patients suffering from neuropathy experience chronicpain and other symptoms which can be relieved with the method of thepresent invention. Patients suffering from multiple sclerosis or spinalcord injury experience spasticity and other symptoms that can berelieved with the method of the present invention. The methods of thepresent invention can also be used to relieve symptoms associated withdystonia and malignant tumors. The methods of the present invention canalso be used to relieve symptoms of stroke, head injuries,neurodegenerative disorders, and other conditions, diseases, anddisorders associated with the N-methyl-D-aspartate receptor. Still otherdiseases and disorders that the present invention may prove useful intreating include Huntington's disease, arthritis, nervous-tissueinflammation, vascular inflammation, inflammatory bowel disease, andother inflammation-related conditions. The mechanism by which symptomsare relieved is not particularly critical to the practice of the presentinvention. Illustratively, symptoms can be relieved by directly treatingthe underlying illness or by blocking the biological pathways by whichthe illness produces the symptoms.

Moreover, the method of the present invention can be used to relievediscomfort associated with the treatment of illness. Illustratively, themethod of the present invention can be used to relieve nausea, vomiting,and/or other discomforts associated with chemotherapy and othertreatment regimens used to treat cancer and other illnesses.

“Relieve,” as used herein, is meant to include complete elimination aswell as any clinically or quantitatively measurable reduction in thesubject's symptoms and/or discomfort.

The method of the present invention involves providing a cannabinoidcomposition. The cannabinoid composition includes at least onecannabinoid selected from the group consisting of Δ⁹-THC, cannabinol,cannabidiol, nabilone, levonantradol, (−)-HU-210, (+)-HU-210,11-hydroxy-Δ⁹-THC, Δ⁸-THC-11-oic acid, CP 55,940, and R(+)-WIN 55,212-2.

“Cannabinoid,” as used herein, is meant to include compounds whichinteract with the cannabinoid receptor and various cannabinoid mimetics,such as certain tetrahydropyran analogs (e.g., Δ⁹-tetrahydrocannabinol,Δ⁸-tetrahydrocannabinol,6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol,3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one,(−)-(3S,4S)-7-hydroxy-Δ6-tetrahydrocannabinol-1,1-dimethylheptyl,(+)-(3S,4S)-7-hydroxy-Δ6-tetrahydrocannabinol-1,1-dimethylheptyl,11-hydroxy-Δ⁹-tetrahydrocannabinol, and Δ⁸-tetrahydrocannabinol-11-oicacid)); certain piperidine analogs (e.g.,(−)-(6S,6aR,9R,10aR)-5,6,6a,7,8,9,10,10a-octahydro-6-methyl-3-[(R)-1-methyl-4-phenylbutoxy]-1,9-phenanthridinediol1-acetate)), certain aminoalkylindole analogs (e.g.,(R)-(+)-[2,3-dihydro-5-methyl-3-(−4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone),certain open pyran ring analogs (e.g.,2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenedioland4-(1,1-dimethylheptyl)-2,3′-dihydroxy-6′alpha-(3-hydroxypropyl)-1′,2′,3′,4′,5′,6′-hexahydrobiphenyl),as well as their pharmaceutically acceptable salts, solvates,metabolites (e.g., cutaneous metabolites), and metabolic precursors.Further examples of “cannabinoids” include those compounds described inthe references cited below.

“Δ⁹-THC,” as used herein, is meant to refer to Δ⁹-tetrahydrocannabinolas well as to its pharmaceutically acceptable salts, solvates,metabolites (e.g., cutaneous metabolites), and metabolic precursors.Δ⁹-tetrahydrocannabinol is marketed under the generic name “dronabinol.”

“Cannabinol,” as used herein, is meant to refer to6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol as well as topharmaceutically acceptable salts, solvates, metabolites (e.g.,cutaneous metabolites), and metabolic precursors of6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol. The synthesis of6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol is described in, forexample, Novak et al., Tetrahedron Letters, 23:253 (1982), which ishereby incorporated by reference.

“Cannabidiol,” as used herein, is meant to refer to2[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediolas well as to pharmaceutically acceptable salts, solvates, metabolites(e.g., cutaneous metabolites), and metabolic precursors of2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol.The synthesis of2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediolis described, for example, in Petilka et al., Helv. Chim. Acta, 52:1102(1969) and in Mechoulam et al., J. Am. Chem. Soc., 87:3273 (1965), whichare hereby incorporated by reference.

“Nabilone,” as used herein, is meant to refer to3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9-H-dibenzo[b,d]pyran-9-oneas well as to pharmaceutically acceptable salts, solvates, metabolites(e.g., cutaneous metabolites), and metabolic precursors of3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one.3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-oneis approved for use in the United Kingdom for treating nausea andvomiting associated with chemotherapy, and its preparation is described,for example, in U.S. Pat. No. 3,968,125 to Archer, which is herebyincorporated by reference.

“Levonantradol,” as used herein, is meant to refer to(−)-(6S,6aR,9R,10aR)-5,6,6a,7,8,9,10,10a-octahydro-6-methyl-3-[(R)-1-methyl-4-phenylbutoxy]-1,9-phenanthridinediol1-acetate, as well as to pharmaceutically acceptable salts, solvates,metabolites (e.g., cutaneous metabolites), and metabolic precursors of(−)-(6S,6aR,9R,10aR)-5,6,6a,7,8,9,10,10a-octahydro-6-methyl-3-[(R)-1-methyl-4-phenylbutoxy]-1,9-phenanthridinediol1-acetate.(−)-(6S,6aR,9R,10aR)-5,6,6a,7,8,9,10,10a-octahydro-6-methyl-3-[(R)-1-methyl-4-phenylbutoxy]-1,9-phenanthridinediol1-acetate is particularly useful in pain control, and its synthesis isdescribed in Belgian Pat. No. 854,655, which is hereby incorporated byreference; in U.S. Pat. Nos. 4,206,225, 4,232,018, and 4,260,764, eachto Johnson, which are hereby incorporated by reference; in U.S. Pat. No.4,235,913 to Johnson et al., which is hereby incorporated by reference;in U.S. Pat. No. 4,243,674 to Bindra, which is hereby incorporated byreference; and in U.S. Pat. Nos. 4,263,438, 4,270,005, and 4,283,569,each to Althuis et al., which are hereby incorporated by reference.

“(−)-HU-210,” as used herein, is meant to refer to(−)-(3S,4S)-7-hydroxy-Δ⁶-tetrahydrocannabinol-1,1-dimethylheptyl as wellas to pharmaceutically acceptable salts, solvates, metabolites (e.g.,cutaneous metabolites), and metabolic precursors of(−)-(3S,4S)-7-hydroxy-Δ⁶-tetrahydrocannabinol-1,1-dimethylheptyl.(−)-(3S,4S)-7-hydroxy-Δ⁶-tetrahydrocannabinol-1,1-dimethylheptyl isparticularly useful in pain control, and its preparation is described inU.S. Pat. Nos. 4,876,276 and 5,521,215, each to Mechoulam et al., whichare hereby incorporated by reference.

“(+)-HU-210,” as used herein, is meant to refer to(+)-(3S,4S)-7-hydroxy-Δ⁶-tetrahydrocannabinol-1,1-dimethylheptyl as wellas to pharmaceutically acceptable salts, solvates, metabolites (e.g.,cutaneous metabolites), and metabolic precursors of(+)-(3S,4S)-7-hydroxy-Δ⁶-tetrahydrocannabinol-1,1-dimethylheptyl.(+)-(3S,4S)-7-hydroxy-Δ⁹-tetrahydrocannabinol-1,1-dimethylheptyl issometimes referred to as HU-211 and/or dexanabinol; it is an antagonistof the N-methyl-D-aspartate receptor; and its preparation is describedin U.S. Pat. Nos. 4,876,276 and 5,521,215, each to Mechoulam et al.,which are hereby incorporated by reference.

“11-hydroxy-Δ⁹-THC,” as used herein is meant to refer to11-hydroxy-Δ⁹-tetrahydrocannabinol as well as to its pharmaceuticallyacceptable salts, solvates, metabolites (e.g., cutaneous metabolites),and metabolic precursors. 11-hydroxy-Δ⁹-tetrahydrocannabinol is a morehydrophilic, psychoactive metabolite of Δ⁹-tetrahydrocannabinol, and itslaboratory synthesis has been described in Siegel et al., J. Org. Chem.,54:5428 (1989), which is hereby incorporated by reference.

“Δ⁸-THC-11-oic acid” as used herein, is meant to refer toΔ⁸-tetrahydrocannabinol-11-oic acid, as well as to its pharmaceuticallyacceptable salts, solvates, metabolites (e.g., cutaneous metabolites),and metabolic precursors. Δ⁸-tetrahydrocannabinol-11-oic acid is anaturally occurring derivative of6a,7,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol(which is a minor component of Cannabis sativa) and is produced from6a,7,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-olvia a series of biotransformations mediated primarily by mammalian liverenzymes. Δ⁸-tetrahydrocannabinol-11-oic acid can also be producedsynthetically by reference to the synthetic schemes set forth in U.S.Pat. No. 6,162,829 to Burstein, which is hereby incorporated byreference. Δ⁸-tetrahydrocannabinol-11-oic acid is more hydrophilic than6a,7,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol,and it has analgesic activity.

“CP 55,940,” as used herein, refers to 4-(1,1-dimethylheptyl)-2,3′dihydroxy-6′alpha-(3-hydroxypropyl)-1′,2′,3′,4′,5′,6′-hexahydrobiphenyl,as well as to its pharmaceutically acceptable salts, solvates,metabolites (e.g., cutaneous metabolites), and metabolic precursors.4-(1,1-dimethylheptyl)-2,3′-dihydroxy-6′alpha-(3-hydroxypropyl)-1′,2′,3′,4′,5′,6′-hexahydrobiphenyl is sometimes referred to as(−)-cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol,and it is commercially available from Tocris Cookson, Inc., Ellisville,Mo. Its preparation has been described in U.S. Pat. No. 4,371,720 toJohnson et al. and U.S. Pat. No. 4,663,474 to Urban, which are herebyincorporated by reference.

“R(+)-WIN 55,212-2,” as used herein, refers to(R)-(+)[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone,as well as to its pharmaceutically acceptable salts, solvates,metabolites (e.g., cutaneous metabolites), and metabolic precursors.(R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone(in its mesylate form) is commercially available, for example, fromTocris Cookson, Inc., Ellisville, Mo., and from Research BiochemicalsInternational, Natick, Mass.

The cannabinoid composition can further include one or more additionalcannabinoids. The one or more additional cannabinoids can be selectedfrom the aforementioned list of cannabinoids or it (they) can beselected from cannabinoids which are not contained in the aforementionedlist, such as Δ⁸-THC, high affinity cannabinoid receptor agonists (otherthan R(+)-WIN 55,212-2 and CP 55,940), and the like. Illustratively, thecannabinoid composition can include two or more cannabinoids, each beingselected from the group consisting of z\9-THC, cannabinol, cannabidiol,nabilone, levonantradol, (−)-HU-210, (+)-HU-210, 11-hydroxy-Δ⁹-THC,Δ⁸-THC-11-oic acid, CP 55,940, and R(+)-WIN 55,212-2.

“Metabolic precursors” of cannabinoids, as used herein, are meant toinclude prodrugs and other materials that are metabolized in thesubject's body (e.g., cutaneously or systemically or both) to acannabinoid or an active cannabinoid mimetic. Suitable metabolicprecursors include those that are less lipophilic (i.e., more watersoluble) relative to the cannabinoid into which they are metabolized.Examples of such metabolic precursors include those described in, forexample, U.S. Pat. No. 5,847,128 to Martin et al., which is herebyincorporated by reference.

“Metabolites” of cannabinoids, as used herein, are meant to includecompounds which are produced by the metabolic processes (e.g., cutaneousmetabolic processes and/or systemic metabolic processes) of thesubject's body. Suitable metabolites can be identified, for example, bystudying the kinetics of drug enzymatic metabolism in skin homogenates.Illustratively, skin homogenates can be prepared from 250-μm dermatomedfresh healthy abdominal plastic surgery samples. The skin is homogenized(e.g., using a Polytron tissue homogenizer and ground glass homogenizerfitted with a glass pestle) in4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (“HEPES”)-bufferedHanks' balanced salt solution. Whole homogenates can be used for thesestudies or, if significant mitochondrial or nuclear metabolism is foundnot to occur (e.g., by comparing the degree of metabolism in thesupernatant the degree of metabolism in the whole homogenate), thestudies can be carried out on only the supernatant fraction. The drug(solubilized in, for example, buffer, ethanol, dimethylsulfoxide, orcombinations thereof) is then incubated with the homogenate (orsupernatant) along with NADPH (or a generating system), NADH, MgCl₂, andbovine serum albumin. The total volume of ethanol in the reactionmixture should be small (e.g., under 2%) to help minimize ethanol'sdetrimental effects on the enzymes. After incubating for a period oftime, the reaction is terminated with 15% trichloroacetic acid, and thedrug and its metabolites are obtained by solid-phase extraction. Themetabolite or metabolites formed can then be identified and assayed byany suitable method (e.g., HPLC).

As one skilled in the art will recognize, optimization of the method ofthe present invention will involve consideration of a variety of factorsin selecting the cannabinoid to be used. One such factor is skinpermeability. Several physicochemical factors influence the ability ofcannabinoids to penetrate the skin. These include the cannabinoid'smolecular weight, its molecular volume, its lipophilicity, its hydrogenbonding potentials, its polarity, etc.

As indicated above, once the cannabinoid composition is provided, thecannabinoid is delivered transdermally to the subject, for example, byiontophoresis; by phonophoresis; by using microneedle technologies; byapplying the cannabinoid as a topical cream, salve, ointment, or othertopical formulation; and/or by using delivery devices such as bandages,patches, and/or the like. Generally speaking, transdermal deliveryinvolves contacting the cannabinoid composition with the subject's skinunder conditions effective for at least one of the provided cannabinoidsto penetrate the skin.

Illustratively, the cannabinoid composition can be formulated as atopical cream, salve, or ointment. The topical formulations can includeinert diluents and carriers as well as other conventional excipients,such as wetting agents, preservatives, and suspending and dispersingagents. In addition to the above, generally non-active components,topical formulations containing the cannabinoid composition can furtherinclude other active materials, particularly, active materials whichhave been identified as useful in the treatment of pain, discomfort, orother conditions associated with a subject's illness and which canusefully be delivered transdermally to the subject. For instance, suchother active materials can include analgesics, such as opiates and otheranalgesic active materials which operate on non-cannabinoid receptors.Where, for example, opiates are included, transdermally deliverableopiates are particularly preferred. One example of a transdermallydeliverable opiate is fentanyl. The topical formulation can be applieddirectly to the skin and then optionally covered (e.g., with a bandageof gauze) to minimize the likelihood of its being disturbed.Alternatively, the topical formulation can be coated on the surface of abandage, gauze, etc., and the bandage, gauze, etc. can then be appliedto the skin of the subject such that the topical formulation is indirect contact with the subject's skin.

Alternatively, the cannabinoid can be delivered transdermally to thesubject by formulating the cannabinoid composition into a bandage, pad,or other type of patch which can be applied to the subject's skin.

Illustratively, matrix-type transdermal patches, in which the selectedcannabinoid is disposed in an adhesive matrix, can be employed. Thematrix-type transdermal patch can further include other cannabinoids andother active materials (e.g., analgesics, such as opiates) fortransdermal delivery to the subject with the selected cannabinoid.Suitable adhesives for use in such matrix-type transdermal patchesinclude polyisobutylenes, acrylates, silicone, and combinations thereof.

Still other patches suitable for use in the practice of the presentinvention include those described in U.S. Pat. No. 5,223,262 to Kim etal., which is hereby incorporated by reference.

In another illustrative embodiment, the bandage, pad, or other type ofpatch can be one which is capable of controlling the release of thecannabinoid such that transdermal delivery of the cannabinoid to thesubject is substantially uniform and sustained over a period of at least12 hours, such as at least 24 hours, at least 48 hours, and/or at least4 days. Such a bandage, pad, or other type of patch which can be used inthe practice of the method of the present invention can take the form ofan occlusive body, such as the occlusive body described below. Inpractice, the occlusive body which includes the cannabinoid ispositioned on the subject's skin under conditions effective totransdermally deliver the selected cannabinoid to the subject's skin.Such conditions can include, for example, positioning the occlusive bodyon a portion of the subject's skin which is not covered with hair; wherenecessary, shaving the hair from the selected portion of the subject'sskin; and/or orienting the occlusive body on the skin such that thecannabinoid, when released from the occlusive body, contacts thesubject's skin.

In another aspect thereof, the present invention, relates to anocclusive body which includes a cannabinoid; an impermeable backing; anda rate-controlling microporous membrane. The backing and the membranedefine a cavity therebetween, and the cannabinoid is disposed withinthis cavity.

An occlusive body in accordance with the present invention and that issuitable for use in the practice of the method of the present inventionis illustrated in FIG. 1.

Referring now to FIG. 1, there is illustrated occlusive body 10.Occlusive body 10 includes impermeable backing 16 having optionalpolyester face 18, cannabinoid composition 22, and rate-controllingmicroporous membrane 24. Rate-controlling microporous membrane 24 isshown heat-sealed around the periphery of its upper face to optionalpolyester face 18 of impermeable backing 16. However, other methods ofsealing rate-controlling microporous membrane 24 to impermeable backing16 (or to optional polyester face 18 of impermeable backing 16) can beemployed. Impermeable backing 16 is illustrated as including optionalaluminized layer 20 on the outer face thereof. Impermeable backing 16and rate-controlling microporous membrane 24 define cavity 26, andcannabinoid composition 22 is disposed in cavity 26. Over time, thecannabinoid contained in cannabinoid composition 22 permeates throughrate-controlling microporous membrane 24 and optional adhesive layer 14,which is illustrated as being coated on the lower face ofrate-controlling microporous membrane 24.

As indicated above, cannabinoid composition 22 contains at least onecannabinoid. Cannabinoids for use in the occlusive body of the presentinvention can be selected from the group consisting of Δ⁹-THC, Δ⁸-THC,cannabinol, cannabidiol, nabilone, levonantradol, (−)-HU-210,(+)-HU-210, 11-hydroxy-Δ⁹-THC, Δ⁸-THC-11-oic acid, CP 55,940, andR(+)-WIN 55,212-2. Preferably, cannabinoids for use in the occlusivebody of the present invention are selected from the group consisting ofcannabinol, cannabidiol, nabilone, levonantradol, (−)-HU-210,(+)-HU-210, 11-hydroxy-Δ⁹-THC, Δ⁸-THC-11-oic acid, CP 55,940, andR(+)-WIN 55,212-2. Mixtures of these and other cannabinoids can also beemployed. Preferably, the cannabinoid is selected such that it issufficiently hydrophobic to pass through rate-controlling microporousmembrane 24. In addition, cannabinoid composition 22 can also includeother inert or active materials, such as those discussed above withregard to topical formulations and/or such as those described below.

Cannabinoid composition 22 can include an aqueous medium, which cancontain a water- and oil-miscible solvent. The cannabinoid compositioncan also contain a material which enhances the cannabinoid's permeationof the skin. Depending on the nature of the chosen solvent, the solventcan also act as the permeation enhancer, or a separate permeationenhancer having the desired miscibility can be added to the cannabinoidcomposition. Illustrative permeation enhancers that can be used in theocclusive bodies of the present invention include ethanol and oleicacid. Preferably the cannabinoid is present together with at least onediluent so that the cannabinoid accounts for no more than about 25% byweight of the contents of the occlusive body's cavity.

The cannabinoid composition can also include one or more inhibitors ofcannabinoid metabolism, particularly in cases where inhibition ofcutaneous metabolism is needed to increase therapeutic drug levels. Suchinhibitors of cannabinoid metabolism can include inhibitors of the P450enzymes or other identified critical enzymatic processes. Suitableinhibitors of cannabinoid metabolism include, for example, essentialoils which inhibit the activity of cytochrome P450 3A in the skin, suchas those described in U.S. Pat. No. 5,716,928 to Benet et al., which ishereby incorporated by reference. Some of these essential oils may alsoact as transdermal penetration enhancers, thus providing a dualmechanism of percutaneous penetration increase.

Rate-controlling microporous membrane 24 can optionally be made of asingle-ply material, or it can be made of a multi-ply material. Only theinner layer of such a membrane needs to be hydrophobic (in the case thatthe cavity contents are hydrophilic) or hydrophilic (in the case thatthe cavity contents are hydrophobic). Thus, in one embodiment, anadditional permeable membrane is in contact with exterior surface 28 ofrate-controlling microporous membrane 24, and the additional permeablemembrane has wetting properties which are the same as, or different fromthe wetting properties of rate-controlling microporous membrane 24.

It is believed that the greater the difference in wetting propertiesbetween the cavity contents and rate-controlling microporous membrane 24(or the innermost layer of rate-controlling microporous membrane 24 if amulti-ply membrane is used), the wider the range of useful solvents andthe more linear the release of the drug. Accordingly, it is desirable toemploy either a strongly hydrophobic or a strongly hydrophilicrate-controlling microporous membrane 24 (or the innermost layer of therate-controlling microporous membrane 24 if a multi-ply membrane isused) in conjunction with strongly hydrophilic cavity contents andstrongly hydrophobic cavity contents, respectively. It should be notedthat the cavity contents can be made hydrophilic by addingsurface-active agent, such as an anionic surface-active agent (e.g.,sodium lauryl sulphonate), a cationic surface active agent (e.g.,cetrimide), or a non-ionic surface active agent (e.g., TWEEN 20®).

Occlusive body 10 can also have an outer layer of an imperviousmaterial, such as a layer of aluminum foil or other metal or plasticlaminate, to prevent seepage or leaching of the contents of the cavity26. The cavity side of rate-controlling microporous membrane 24 can befaced with an area-reducing mesh formed, for example, from a non-wovenfabric or from a perforated impermeable material such as aluminum foil.

Rate-controlling microporous membrane 24 can be made of any suitablemembrane material, such as a hydrophobic and microporous membranematerial, for example, CELGARD® 2500 polypropylene of thickness 0.025 mm(1 mil) and pore size 0.4-0.04 microns.

Exterior surface 28 of rate-controlling microporous membrane 24 (i.e.,the face distant from cavity 26) can optionally be coated with adhesivelayer 14, for example, having a thickness of, for example, about 30micrometers. Any suitable dermatologically acceptable pressure sensitiveadhesive that does not react chemically with the cavity contents orprevent passage of the cannabinoid through the membrane from beingrate-controlling can be used for adhesive layer 14. Thus, the adhesivecan be chosen such that the cannabinoid passes reasonably rapidlythrough adhesive layer 14, though some retardation is acceptable inpractice. The adhesive can be, for example, an elastomeric siliconepolymer. Other suitable adhesives include polyisobutylenes andacrylates. Optional release liner 12, such as a sheet of release coatedpaper or other material, can be used to cover adhesive layer 14 untilthe occlusive body 10 is to be used, thus preventing cannabinoidpermeation prior to contacting occlusive body 10 with the subject'sskin. Immediately prior to use, release liner 12 is stripped fromadhesive layer 14, and occlusive body 10 is adhered to the subject'sskin (e.g., of the arm) (not shown) by the exposed adhesive layer 14.

It is to be understood that adhesive layer 14 is but one of manysuitable ways for attaching the occlusive body 10 to the subject's skin.For example, as an alternative to using adhesive layer 14, a separatetape or bandage material can be employed to attach the occlusive body ofthe present invention to the subject's skin.

The occlusive body of the present invention can further include aviscous flowable gel which is disposed within the occlusive body'scavity and which immobilizes the cannabinoid within the cavity. Such gelformulations can be useful to reduce the likelihood of abrupt absorptionof the cannabinoid in the event of sudden rupture of the cavity andrelease of the cavity contents onto the skin. Suitable gel formulationscan be achieved by making the viscosity of the cavity contentssufficiently high such that they are resistant to spreading in the eventof cavity puncture. Illustratively, methyl cellulose in water can beused as a viscosity modifier in such gel formulations. In certainsituations, the use of methyl cellulose in combination with thecannabinoid composition can also be advantageous in that the methylcellulose can also function as a surface active agent to enhance thehydrophilicity of the cavity contents.

The cannabinoid may be mixed with up to 2% (typically about 1% byweight) of oil of Melaleuca alternifolia (Tea Tree Oil) or anotherbactericide before being introduced into the cavity. Tea Tree Oil oranother bactericide can also be mixed with an adhesive to form a layercovering a face of the rate-controlling microporous membrane remote fromthe cavity. The major constituents of Tea Tree Oil are 1-terpinen-4-oland terpinene with minor amounts of 1,8-cineole and p-cymene, and itsproperties, together with those of other Australian essential oils, aredescribed in Beylier, Perfumer & Flavorist, 4:23 (April/May 1979), whichis hereby incorporated by reference. Tea Tree Oil may be substituted byother essential oils that possess antibacterial qualities. Preferablythe Tea Tree Oil is present in an amount of from 0.05% to 2% by weightof the liquid contents of the cavity.

In this invention, the rate-controlling microporous membrane can be ahydrophobic microporous material, such as hydrophobic microporouspolypropylene or polyethylene. The cavity contents can illustrativelyinclude, in addition to the cannabinoid, a wetting agent water based gelformed, for example, using methyl cellulose. As a further illustrationof an occlusive body of the present invention, the rate-controllingmicroporous membrane can be a hydrophobic microporous polypropylenemembrane and the cavity can contain, in addition to the cannabinoid, awater-based gel containing an amount of methyl cellulose (e.g., 5%)which gives a linear release of the cannabinoid while retaining waterand solids. It may be expedient to dissolve the cannabinoid in anappropriate pharmaceutically acceptable vehicle, which will carry theactive substance through the rate-controlling microporous membrane.Moreover, the rate of delivery of the cannabinoid through therate-controlling microporous membrane into the blood stream of thesubject can be varied by varying the surface area, thickness, andcomposition of the membrane; by varying the weight ratio ofcannabinoid-to-vehicle; and by varying the hydrophilicity of the cavitycontents.

In this manner, the dosage rate can be varied over a wide range bysuitable adjustment of various parameters of the occlusive body, whilemaintaining a substantially uniform dosage rate. However, in order tominimize variations in dosage rate between different patients owing tovariations in their skin resistance, the permeability of therate-controlling microporous membrane is preferably less than (e.g.,from 0.75 to 0.9 times) the permeability of the least permeable skinlikely to be encountered in the use of the occlusive body.

Further details with regard to the construction and configuration ofocclusive bodies suitable for use in the practice of the presentinvention can be found, for example, in U.S. Pat. No. 5,254,346 toTucker et al., which is hereby incorporated by reference. It should beunderstood that, in addition to the aforementioned cannabinoid orcombination of cannabinoids, other active materials, such as opiates andother analgesics, can be contained in the occlusive body's cavity anddelivered transdermally through the rate-controlling microporousmembrane together with the cannabinoid or cannabinoid combination.

The present invention, in yet another aspect thereof, relates to amethod for assessing the permeability of skin to cannabinoids,particularly lipophilic cannabinoids.

The method includes providing a skin sample. Suitable skin samples canbe obtained, for example from abdominal plastic surgery procedures.Typically, the sample is dermatomed to a thickness of from 150-600 μm,preferably from 200-300 μm, more preferably around 250 μm. Thedermatomed skin sample is generally substantially planar and has a firstsurface and an opposing second surface.

The method further includes providing a donor solution which includesthe cannabinoid to be studied dissolved in a suitable vehicle.Preferably, the vehicle is chosen such that a substantial concentrationis achieved and such that, at this substantial concentration, thecannabinoid forms a near (e.g., greater than 80%) saturated solution.

The method further includes providing a receiver solution which includesfrom 0.1 to 5% of a polyoxyethylene oleyl ether. Suitablepolyoxyethylene oleyl ethers include polyoxyethylene 20 oleyl ether,e.g., BRIJ® 98, which is available from Sigma (St. Louis, Mo.).Illustratively, the concentration of polyoxyethylene 20 oleyl ether canbe from about 0.1 to about 5%, such as from about 0.2 to about 4%, fromabout 0.2 to about 3%, from about 0.3 to about 3%, from about 0.4 toabout 3%, from about 0.5 to about 3%, from about 0.5 to about 5%, and/orabout 0.5%.

In the practice of the method of the present invention, the skin sampleis disposed between the donor solution and the receiver solution suchthat the skin sample separates the donor solution and the receiversolution, such that the donor solution is in contact with the skinsample's first surface, and such that the receiver solution is incontact with the skin sample's second surface. Preferably, the skinsample is arranged such that the epidermal side of the skin sample is incontact with the donor solution. The arrangement of donor solution/skinsample/receiver solution can be held in place using any suitableapparatus. One suitable commercially available apparatus is thePermeGear In-Line Diffusion Cell, which is available from PermeGear,Inc. (Riegelsville, Pa.). Typically the donor solution is permitted toremain in contact with the skin sample for a period of time ranging fromseveral minutes to several weeks (e.g., 2-4 days), during which timesome portion of the cannabinoid permeates through the skin sample andinto the receptor solution. The method further includes detectingcannabinoid present in the receiver solution, such as by chromatography(e.g., HPLC). The method can further include quantifying the amount ofcannabinoid present in the receiver solution, calculating permeabilityrates, lag times, and other such useful information, as describedfurther below.

The present invention is further illustrated with the followingexamples.

Example 1 Delivery of WIN 55,212-2 Across Skin

WIN 55,212-2 Mesylate (melting point 244-245° C.) was purchased fromResearch Biochemicals International, Natick, Mass. Reagent-gradechemicals were used as received.

The skin permeation study was carried out using skin excised duringabdominal reduction surgery. The skin sample was harvested from theabdomen using a Padgett dermatome set to 250 μm; the skin sample wasfrozen at −20° C. for one week. The frozen skin sample was thawed andused at the 250 μm split-thickness for the diffusion study. ThreePermeGear In-Line Flow Cells were used for the skin permeation study.The receiver fluid was 6% BRIJ® 98 (Polyoxyethylene 20 Oleyl Ether), inorder to increase the partitioning of this extremely lipophilic druginto the receiver. The receiver fluid was pumped through the diffusioncells at a rate of one milliliter per hour. The receiver samples wererefrigerated until HPLC analysis. The temperature of the diffusion cellswas maintained at 32° C. with a circulating water bath. The diffusionexperiment was initiated by charging the donor compartment with 0.25 mLof WIN 55,212-2 Mesylate in propylene glycol (50 mg/mL). Water was notused as the drug vehicle, in order to prevent the low water solubilityof WIN 55,212-2 from significantly influencing the diffusion rate.

Samples were analyzed using a HPLC system which consisted of a Waters717 Autosampler, 501 Pumps, and a 484 Tunable UV Absorbance Detectorwith Millennium Chromatography Software. A reversed phase Beckman 5 μmparticle 4.6 mm×25 cm C-18 column was used with the UV detector set at awavelength of 215 nm. The mobile phase consisted of 0.05 M monobasicpotassium phosphate:acetonitrile (300 mL:700 mL) at a flow rate of 2mL/min. The sensitivity of the assay was 10 ng/mL, and the WIN 55,212-2had a retention time of 3.4 minutes. Standard curves exhibited excellentlinearity over the entire concentration range employed in the assays.

Skin permeation data were plotted as the cumulative amount of drugcollected in the receiver compartment as a function of time. The lagtimes and steady-state fluxes were calculated using the terminal, linearportions of these curves. The slopes (J_(s)) through these curves weredetermined using linear regression analysis. In all cases, thecoefficients of determination for the lines were >0.99. A representativepermeation profile is shown in FIG. 2.

Lag times were determined by extrapolating the steady-state curves tothe X-axis. The permeability coefficient was calculated from Fick's lawof diffusion:

${\frac{1}{A}\left( \frac{\left( {m} \right)}{\left( {t} \right)} \right)} = {J_{s} = {K_{p}\Delta \; C}}$

where J_(s) is the steady-state flux (e.g., in g/cm²/h), M is thecumulative amount of drug permeating the skin, A is the area of theskin, K_(p) is the effective permeability coefficient in cm/h, and ΔC isthe difference in concentrations of cannabinoid in the donor andreceiver compartments.

The skin permeation experiment was run for 48 hours, during which time asteady-state flux was obtained. The diffusion lag time for theseexperiments averaged to be 24 hours. Although the donor compartment didnot contain a saturated drug solution, the drug depletion from the donorcompartment was minimal (<1%). The mean flux of these diffusionexperiments was found to be 2.6 (±1.1 standard deviation, n=3) μg/cm²/h.The effective permeability coefficient, P, was calculated using Fick'slaw of diffusion as 1.4×10⁻⁸ cm/s.

These diffusion values are similar in magnitude to the reportedfull-thickness human skin Δ⁸-THC flux rate of 3.5 μg/cm²/hr, and thepermeability coefficient of 3.6×10⁻⁸ cm/s reported in Touitou et al.,Int. J. Pharm., 43:9-15 (1988), which is hereby incorporated byreference. The WIN 55,212-2 flux would have been a higher value ifenough drug had been available to apply a saturated solution to theskin. One of the practical goals elucidated from this skin permeationstudy is to choose a vehicle that solubilizes enough drug, but not somuch drug that making a saturated solution becomes excessivelyexpensive.

Example 2 Optimization of In Vitro Experimental Conditions for StudyingPermeation Through and Metabolism of Cannabinoids by Human Skin

The permeability of human skin has been studied for several decades. Theskin consists of two major layers, the outer epidermis and the innerdermis. The stratum corneum (“SC”), the outermost 10-20 μm of theepidermis, is responsible for the skin's excellent diffusionalresistance to the transdermal delivery of most drugs. Most of the skin'senzymatic activity lies in the basal cell layer of the viable epidermis.Fibrous collagen is the main structural component of the dermis. Theskin vasculature is supported by this collagen and lies a few micronsunderneath the epidermis. Basically, it is here that permeation ends andsystemic uptake begins. Many researchers have developed skinpermeability relationships based on the physicochemical parameters(molecular weight, molecular volume, lipophilicity, hydrogen-bondingpotentials, polarity, etc.) of skin penetrants. However, when dealingwith transdermal administration of cannabinoids, these skin permeabilityrelationships need to be modified to take into account the potentialcomplications of extreme lipophilicity and concurrent metabolism ofthese drugs.

Generally speaking, cutaneous metabolism of transdermally delivereddrugs is a potential pitfall to therapeutic success. For example,transdermally delivered testosterone and estradiol undergo significantcutaneous metabolism. However, as discussed further below, cutaneousmetabolism of cannabinoids can be exploited when designing transdermalprodrugs or when delivering drugs that are converted to activemetabolites. For example, it is likely that cannabinoids undergosignificant metabolism as they diffuse through viable human skin. Thelow oral bioavailability of dronabinol (0.1-0.2) is an indication thatextensive metabolism may occur; however, some compounds that undergoextensive systemic metabolism do not undergo biotransformation duringtransit through the skin (Collier et al., “Cutaneous Metabolism,” pp.67-83 in Bronaugh et al., eds., IN VITRO PERCUTANEOUS ABSORPTION:PRINCIPLES, FUNDAMENTALS, AND APPLICATIONS, Boca Raton, Fla.: CRC Press(1991), which is hereby incorporated by reference). Most enzymes in theskin have 1-10 percent of the enzymatic specific activity they have inthe liver, although other enzymes have equivalent specific activity inboth organs. Oxidation generates the main metabolites of Δ⁸-THC andΔ⁹-THC, by aliphatic hydroxylation at the eleven-position carbon,further oxidation to an 11-oic acid, and subsequent glucuronidation.Nabilone fauns a diol by reduction at the 9-keto group. Levonantradol israpidly deacetylated. Evidence suggests that CP 55,940 may undergo sidechain hydroxylation.

Selection and optimization of cannabinoids for transdermal deliveryrequires an understanding of their cutaneous metabolism. Furthermore,since skin metabolism of topical in vivo studies cannot easily bedistinguished from blood, liver, or other tissue metabolism, cutaneousmetabolism is better studied in vitro. However, the success of any suchin vitro study depends heavily on finding ideal conditions to simulatein vivo conditions, especially in maintaining tissue viability. Thus,selection of an optimal receiver solution is critical to the success ofany such in vitro studies.

Therefore, applicant has undertaken a study to optimize in vitroexperimental conditions for the measurement of Δ⁹-tetrahydrocannabinolacross human skin. Additionally, intact and stripped skin were alsocompared in order to determine if the SC provided significant resistanceto the diffusion of highly lipophilic Δ⁹-tetrahydrocannabinol. The studyand results are described below.

Δ⁹-tetrahydrocannabinol in 95% ethyl alcohol was obtained in ampulesfrom National Institute of Drug Abuse (Research Triangle Park, N.C.).Hanks balanced salts modified powder, Bovine Albumin Fraction V (“BSA”),potassium phosphate monobasic anhydrous, sodium bicarbonate, andPolyoxyethylene 20 Oleyl Ether (BRIJ 98®) were obtained from Sigma (St.Louis, Mo.). Propylene glycol,4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (“HEPES”),triethylamine (“TEA”), gentamycine sulfate, acetonitrile (HPLC grade)and 20 mL Scintillation vials were obtained from Fisher Scientific(Fairlawn, N.J.).

The following instruments and accessories were used in this study.PermeGear flow-through diffusion cells having a surface area of 0.95 cm²were obtained from PermeGear (Hellertown, N.J.). Water Bath 280 seriesand Shallow Form Shaker Bath were obtained from Precision (Winchester,Va.). Isotemp 2006S water circulator was obtained from Fisher Scientific(Fairlawn, N.J.). Retriever IV fraction collector was obtained from ISCOInc. (Lincoln, Nebr.). PUMPPRO® MPL static pump was obtained from WatsonMarlow (Wilmington, Mass.). Sartoris BP211D model balance was obtainedfrom Sartoris (Edgewood, N.Y.). Padgett Dermatome was obtained fromPadgett Instruments (Kansas City, Mo.). HPLC with autosampler (200series model) and UV detector 785A were obtained from Perkin Elmer.Autosampler vials, nonsilanized/silanized were obtained from KimbleGlass (Vineland, N.J.). All glassware employed in the study wassterilized with 70% v/v ethanol/water.

Receiver solutions containing Hanks-HEPES balanced salt solution(“HHBSS”) and BSA were prepared as follows. HHBSS was prepared bydissolving 9.8 g Hanks balanced salt mixture along with 5.96 g of HEPESand 0.35 g of sodium bicarbonate in 1000 mL of Mili-Q distilled water.The pH was adjusted to 7.4 with 1 N HCl or 1 N NaOH, the solution wasfiltered through a Milipore filtration system using a 0.2 μm membrane,and 50 mg of gentamycin was added to minimize microbial contamination.Appropriate amounts of BSA, either 4% or 6% (based on the experimentaldesign), were then dissolved into the resulting solutions to produce theHHBSS/BSA receiver solutions.

Receiver solutions containing BRIJ® 98 were prepared by dissolvingappropriate amounts of BRIJ® 98 (0.5% and 6% w/v) in 1000 mL of Mili-Qdistilled water.

Human skin samples were prepared as follows. Skin tissue samples frompatients having undergone abdominoplasty were obtained from NationalCancer Institute Cooperative Human Skin Tissue Network. The samples weredermatomed immediately upon arrival (usually less than 24 hr afterharvesting) to obtain 250 μm intact skin samples. The samples wereeither used immediately or wrapped and then frozen at −20° C. Therequired fresh tissue portions for immediate use were sliced accordingto diffusion cell disk area. The removed portions were transferredimmediately onto diffusion cell disks that had been previouslysterilized with 70% v/v ethanol/water, making sure that the dermalportions were exposed towards the receiver solution. The disks werefixed onto their holders with the aid to hold the tissue firmly and toavoid any leakage of formulation. The actual thickness of skin used ineach experiment was measured.

Stripped skin samples were obtained from the above-describedabdominoplasty skin as follows. The required skin portion was markedbefore being dermatomed. The SC of the selected portion was removed withhelp of SCOTCH® book tape No. 845. The procedure was repeated (typically10-30 times) to make sure that the SC was removed convincingly. Theresulting stripped skin, thus obtained, was either used immediately orwrapped and frozen at −20° C. The stripped skin samples were then slicedand transferred onto diffusion cell disks as described above. The actualthickness of skin used in each experiment was measured.

When additional intact and stripped skin samples were needed, frozenintact and stripped skin samples were thawed at room temperature, andthe required tissue portions were then sliced and transferred ontodiffusion cell disks as described above.

A Δ⁹-tetrahydrocannabinol formulation was prepared as follows. Suitablealiquots of Δ⁹-tetrahydrocannabinol in 95% absolute ethanol(approximately 0.04 parts ethanol/mL) were transferred to a mixture ofpropylene glycol:water (90:10) and mixed well to obtain 8.59 mg/mL ofdrug concentration in each sample.

The in vitro experiments were carried out under the followingconditions. The receiver solutions were maintained at 37° C. for 30 minprior to conditioning the diffusion cell lines. After cleaning thetransfer tubes with 50% methanol for 1 h, the diffusion lines wereconditioned by pumping the receiver solution through them for at leastfor 1 h. The diffusion cell mounting table (an aluminum block holder)was conditioned to keep the skin surface at 32° C. by circulating awater bath maintained at 37° C. Thereafter, the skin diffusion celldisks were transferred to the mounting table, and the skin diffusioncell disks were equilibrated by circulating a water bath maintained at37° C. for 30 min. The donor cell was loaded with 240 μL of theΔ⁹-tetrahydrocannabinol formulation and was covered with a suitable cap.The receiver solution was pumped through the receiver cell at a flowrate of 1.5 mL/h for either 48 h or 96 h. Samples were collected using afraction collector at 6 h intervals for either 48 h or 98 h, dependingon the study. At the end of each experiment, the tissue was removed fromthe respective diffusion cell disk. Both the epidermal and dermalsurfaces of the removed tissue sample was briefly washed with distilledwater, and excess water was removed with blotting paper. The formulationcovered skin surface of the washed and blotted removed tissue sample wasstripped once with SCOTCH® book tape No. 845 to remove the formulation,and the stripped, washed, and blotted removed tissue sample was slicedto smaller portions. The smaller portions were then transferred to apreviously weighed scintillation vial, the combined weight of thescintillation vials and tissue was measured, and, from this, the weightof the tissue was calculated. The tissue samples were then digestedovernight in 10 mL ACN on a shaker bath to estimate the drug penetrationinto skin layers.

BRIJ® 98 pretreatment studies were carried out as follows. At the end ofregular 48 h diffusion experiment, the samples collected in BRLI® 98receiver solution were immediately removed and, without interruption ofthe experiment, replaced with BSA 4% receiver solution. The experimentwas continued for a further 48 h period against both BRIJ® 98 and BSA 4%controls.

The diffusion samples collected using either 4% or 6% BSA receiversolution were extracted in the following manner. To each sample wasadded 4-fold ACN, and the resulting mixture was vortexed for 1 min, thensonicated for 15 min, then vortexed again for 1 min, and finallycentrifuged at 9000 rpm for 15 min. The supernatant was collected andtransferred to silanized HPLC autosampler vials. 100 μL it of eachsample was injected for each HPLC run, and the recovery was 90%.

The diffusion samples collected using either 0.5% or 6% BRIJ® 98receiver solution were either injected directly into the HPLC apparatusor diluted 1:3 with ACN, vortexed for 1 min, and then injected into theHPLC apparatus. The injection volume was 100 μL, and recovery was 100%.

The diffusion samples were estimated using the following HPLC method. Amobile phase containing 80:20 ACN:phosphate buffer (25 mM KH2PO4+0.1%TEA, pH 3.0), a reverse phase C8 column (BROWNLEE®, 220×4.6 mm,Spheri-5), and a guard column (BROWNLEE®, reverse phase, C8, 15×3.2 mm,7 μm particle size) were employed. The flow rate was 1.5 mL/min. Runtime was 7.0 min, except that all BRIJ® 98 samples were run foradditional 7.0 min after each run time at a flow rate of 2.0 mL/min towash the column of BRIJ® 98 peaks). The detection wavelength was set to215 nm, retention time was 4.0±0.1 min, linearity was 25-1000 ng/mL, andsensitivity was 5 ng/mL.

The data were treated as follows. Permeability coefficients ofΔ⁹-tetrahydrocannabinol were calculated using the steady state skin fluxand the saturation solubility of the compound in the vehicle employed.

FIG. 3 shows the permeability of Δ⁹-tetrahydrocannabinol through humanskin in five subjects in presence of both BSA (4%) and BRIJ® 98 (6%). Itis evident from the data, that permeability of Δ⁹-tetrahydrocannabinolis 2-5 fold higher in presence of BRIJ® 98 solution relative to BSAsolution, except in subject 4. These differences were statisticallysignificant in all subjects (Student's t-test, p<0.05) indicated withasterisk in FIG. 3. No clear pattern between lag times was observed.

The higher permeability of Δ⁹-tetrahydrocannabinol noted with BRIJ® 98(FIG. 3) could be due to possible damage to the skin caused by BRIJ® 98,a surfactant. Therefore, to minimize this possible damage to the skinand to enhance the solubility of drug, results using a low concentrationof BRIJ® 98 (0.5% solution) were compared against the results obtainedusing a 6% BRIJ® 98 solution. The results are set forth in FIG. 4.

Interestingly, similar Δ⁹-tetrahydrocannabinol permeability results wereobtained for the three subjects irrespective of whether 6% BRIJ® 98solution or 0.5% BRIJ® 98 solution was employed, and whateverdifferences exist are not statistically significant (Student's t-test,p<0.05). No particular difference was observed between lag times. Thesefindings demonstrate that one can minimize possible damage to skinwithout adversely affecting the solubility of drug in receiver solutionby using a low (e.g., about 0.1 to about 5%, such as about 0.2 to about4%, about 0.2 to about 3%, about 0.3 to about 3%, about 0.4 to about 3%,about 0.5 to about 3%, and/or about 0.5 to about 5%) concentration ofBRIJ® 98.

Experiments were conducted in which, at the end of BRIJ® 98 pretreatmentperiod (48 h), the receiver solution was changed to HHBSS/BSA (4%). IfBRIJ® was causing damage to the skin sample, this pretreatment stepshould also result in increased drug permeation in presence ofHHBSS/BSA. The results of pretreatment studies performed to understandthe possible damage effects of 6% BRIJ® 98 in three subjects are shownin FIG. 5A. The Δ⁹-tetrahydrocannabinol permeability obtained betweenBRIJ® and BSA solutions demonstrated once again that 6% BRIJ® 98resulted in higher drug permeation through human skin relative to BSApretreatment and BSA control. Tissues pretreated with 6% BRIJ® 98 for 48h followed by a change to BSA (4%) for an additional 48 h exhibitedpermeability values similar to those of 4% BSA control after 96 h. Inaddition, referring now to FIG. 5B, there is no noticeable deviationfrom steady state in any of the permeability profile of 6% BRIJ® 98solutions during 96 h, while, in the pretreated samples, the profiletends to move closer and parallel to the 4% BSA control. No lag timedifferences between the receiver solutions were observed. From the abovediscussion and the data presented in FIGS. 5A and 5B, it is clear thatBRIJ® does not cause any damage to the skin. The one-way ANOVA and Tukeytest comparison of above data suggest that there is significantdifference between the permeability values of BRIJ® 98 and 4% BSAsolutions (this significance being noted in FIG. 5A with an asterisk)and that there is no significant difference between BSA control andpretreated/BSA solutions.

As discussed above, it is known that many drugs are metabolized duringtheir permeation across human skin. To understand this metabolic processfor cannabinoids and to thus be able to choose those cannabinoids thatare likely to be active upon systemic absorption, the receiver solutionshould be such that it not only has appreciable solubility for the drugbut also such that it does not adversely impact on the tissue'sviability. In this context, HHBSS/BSA, being closer in composition tosystemic fluids especially blood, can be considered a better receiversolution. Accordingly, experiments were conducted using 6% BRIJ® 98, 4%BSA, and 6% BSA. The results obtained from this study in four subjectsare shown in FIG. 6. It is clear from the data presented in FIG. 4 that6% BSA has enhanced Δ⁹-tetrahydrocannabinol permeability in all subjectsby some 20-50% relative to 4% BSA (except in subject 3). Additionally,in three out of four subjects in FIG. 6, the permeability differencebetween 6% BSA and 4% BSA was considered to be statistically significant(Student's t-test, p<0.05). No lag time differences between receiversolutions were observed.

It is conventional practice to perform tape strip studies against intactskin to understand clearly the barrier effects of SC. Thus, tape stripstudies for Δ⁹-tetrahydrocannabinol against intact skin were conductedusing the above-identified receiver solutions. The results obtained invarious subjects are shown in FIG. 7. It is clear from FIG. 7 that thepermeability values of tape stripped skin are 2-3 times higher relativeto their intact skin counterparts, and, in the case of 6% BRIJ® 98receiver solution, a six fold difference was observed. Moreover, theobserved mean lag times were found to be shorter for stripped skin(7.8±3.9 h) relative to intact skin (18.0±3.4 h). The Student's t-test(p<0.05) comparison of data suggests that the permeability differenceswere significant in three out of five subjects. This demonstrates thatthe acts as barrier for permeation of Δ⁹-tetrahydrocannabinol molecule.

Example 3 Delivery of2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediolAcross Skin

The flux of2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol(a cannabidiol) (“CBD”) across human skin was measured following theprocedures set forth in Example 2, except that the donor compartment wascharged with CBD in mineral oil (saturated) instead of Example 2'sΔ⁹-tetrahydrocannabinol in propylene glycol (50 mg/mL). Two receiversolutions were employed: 4% BSA and 6% BRIJ® 98. The experiments wererun as in Example 2, and the maximum flux was calculated. The resultsare presented in FIG. 8.

A number of compounds may be useful in enhancing the transdermalpermeation of cannabinoids by increasing the amount of a co-administeredcannabinoid within a patient's skin. Suitable permeation enhancersinclude, for example, propylene glycol monolaurate, diethylene glycolmonoethyl ether, oleoyl macrogolglycerides, caprylocaproylmacrogolglycerides, and oleyl alcohols.

Example 4 Co-Administration of Cannabinoids and Permeation Enhancers

The aim of the experiment was to evaluate the effect of permeationenhancers on human skin permeation of cannabidiol (CBD). The followingpermeation enhancers were used in the study:

-   -   LAUROGLYCOL 90-(Propylene glycol monolaurate 90%)-LG-90    -   TRANSCUTOL HP (Purified diethylene glycol monoethyl ether)-TC-HP    -   LABRAFIL® M 1944 CS (Oleoyl Macrogolglycerides)-LF    -   LABRASOL® (Caprylocaproyl Macrogolglycerides)-LB    -   SUPER REFINED® NOVOL NF (Oleyl Alcohol)-OA

A high-pressure liquid chromatography (HPLC) assay was used for theanalysis of CBD in the samples. The HPLC system consisted of a Waters717 plus Autosampler, Waters 1525 Binary HPLC Pump and Waters 2487 Dualλ Absorbance Detector with Waters Breeze software. A Brownlee C-18reversed-phase Spheri-5 μm column (220×4.6 mm) with a C-18 reversedphase 7 μm guard column (15×3.2 mm) was used with the UV detector set ata wavelength of 215 nm. The mobile phase was comprised of acetonitrile:25 mM phosphate buffer with 0.1% triethylamine pH 3.0 (80:20). The flowrate of the mobile phase was 1.5 mL and 100 μL of the sample wasinjected onto the column. The external standard curve exhibitedexcellent linearity over the entire concentration range employed in theassays.

Human skin harvested during abdominoplasty was used for the diffusionstudies. Skin sections were obtained by using a Padgett Instruments®dermatome set to 250 microns and stored at −20° C. A PermeGearflow-through (In-Line, Riegelsville, Pa.) diffusion cell system was usedfor the skin permeation studies. Trans-epidermal water loss was measured(Evaporimeter EP1™, ServoMed, Sweden) after securing the skin in thecells. Pieces of skin with readings below 10 g/m²/h were used for thediffusion studies. The skin surface in the diffusion cells wasmaintained at 32° C. with a circulating water bath. The receiversolution was HEPES-buffered Hanks' balanced salts with gentamicin (toinhibit microbial growth) containing 40% polyethylene glycol 400 (pH7.4), and the flow rate was adjusted to 1.1 mL/h. An excess quantity ofCBD was added to the donor vehicle (propylene glycol:Hanks' buffer(80:20)) solution with and without permeation enhancers at 6% v/v,sonicated for 10 min, and then applied onto the skin. Excess quantity ofthe drug was used in the donor compartment throughout the diffusionexperiment in order to maintain maximum and constant chemical potentialof the drug in the donor vehicle. Each cell was charged with 0.25 mL ofthe respective drug solution. Samples were collected in 6 h incrementsfor 48 h. All the samples were stored at 4° C. until HPLC analysis.

The cumulative amount of drug collected in the receiver compartment wasplotted as a function of time. The flux value for a given experiment wasobtained from the slope of the steady state portion of the cumulativeamount of drug permeated plotted over time. Apparent permeabilitycoefficient values were computed, as described above, from Fick's FirstLaw of Diffusion:

${\frac{1}{A}\left( \frac{\left( {m} \right)}{\left( {t} \right)} \right)} = {J_{s} = {K_{p}\Delta \; C}}$

Sink conditions were maintained in the receiver throughout theexperiment, so AC was approximated by the drug concentration in thedonor compartment.

Drug disposition in the skin samples was measured at the completion ofthe 48 h experiment. The skin tissue was rinsed with nanopure water andblotted with a paper towel. To remove the drug formulation adhering tothe surface, the skin was tape stripped twice using book tape (Scotch®,3M, St. Paul, Minn.). The skin in contact with the drug was excised,minced with a scalpel and placed in a pre-weighed vial. Drug wasextracted from the skin by equilibrating with 10 mL of ACN in a shakingwater bath overnight at room temperature. Samples were analyzed by HPLCto determine CBD content in micromoles (μmol) of drug per gram of wettissue weight.

Statistical analysis of the in vitro human skin permeation data wasperformed using SigmaStat 2.03. A one-way ANOVA with Tukey post-hocanalysis was used to test the statistical differences among thedifferent treatments.

The results of the permeation studies were as follows:

TABLE 1 Cumulative amount permeated at 48 h Skin Content FormulationFlux (nmol/cm²/h) Lag Time (h) (nmol) (μmol/g) CBD‡*  6:13 ± 0.43 14.19± 1.59  193.21 ± 22.77 22.28 ± 24.47 CBD + LG-90† 11.43 ± 0.76 9.20 ±3.88 422.22 ± 63.27 19.74 ± 8.40  CBD + TC-HP† 14.81 ± 1.08 12.34 ±5.78   503.98 ± 109.94 34.19 ± 20.34 CBD‡  9.16 ± 1.41 9.43 ± 2.47338.11 ± 73.09 9.08 ± 6.12 CBD + LB* 12.45 ± 0.94 4.57 ± 2.72 514.32 ±64.59 24.86 ± 5.33  CBD + OA* 14.69 ± 1.70 5.70 ± 0.00  688.09 ± 154.2937.94 ± 3.66  CBD + LF* 14.90 ± 3.02 1.92 ± 2.05  670.54 ± 184.73 59.03± 26.36 *n = 3 †n = 4 ‡Experiments were run with skim from two differenthuman subjects.

The results of the present study indicated that CBD can be delivered viathe transdermal route and that the permeation enhancers, Lauroglycol-90(Propylene glycol monolaurate 90%), Transcutol-HP (Purified diethyleneglycol monoethyl ether), LABRASOL® (Caprylocaproyl macrogolglycerides),SUPER REFINED® NOVOL NF (Oleyl Alcohol) and LABRAFIL® M 1944 CS (Oleoylmacrogolglycerides) increased the amounts of CBD permeated through humanskin. As shown in Table 1 above and in FIGS. 9 and 10, each enhancer ata 6% v/v concentration in the donor vehicle increased the steady stateflux and cumulative amounts permeated at 48 h significantly (p<0.05)when compared to CBD alone.

A 2.41 and 1.86 fold increase in steady state flux was observed withTranscutol-HP and Lauroglycol-90, respectively, when compared to thesteady state flux of CBD alone. Transcutol-HP significantly increasedthe amounts of CBD permeated through human skin when compared toLauroglycol-90 (p<0.05). A 1.29 fold increase in steady state flux ofCBD was observed with Transcutol-HP when compared to Lauroglycol-90.Whereas, a 1.36, 1.62 and 1.60 fold increases in steady state flux wereobserved with LABRASOL®, LABRAFIL® M 1944 CS and SUPER REFINED® NOVOL NF(Oleyl Alcohol).

FIGS. 11 and 12 show plasma THC and CBD concentrations, respectively,following the separate and coadministration of each. As can be seen, theconcentration of each is higher both initially and over time whencoadministered.

Overall, the results of the present study indicated that significantamounts of CBD could be delivered through human skin in the presence ofpermeation enhancers.

The foregoing description of the preferred embodiments of this inventionhas been presented for purposes of illustration and description. It isnot intended to be exhaustive or to limit the invention to the preciseform disclosed, and obviously, many modifications and variations arepossible. Such modifications and variations that may be apparent to aperson skilled in the art are intended to be included within the scopeof this invention as defined by the accompanying claims.

1. A method for relieving symptoms associated with illness or associatedwith the treatment of illness in a mammalian subject, comprising thesteps of: selecting at least one cannabinoid from the group consistingof: cannabinol, cannabidiol, nabilone, levonantradol, (−)-HU-210,(+)-HU-210, 11-hydroxy-Δ⁹-THC, Δ⁸-THC-11-oic acid, CP 55,940, andR(+)-WIN 55,212-2; selecting at least one permeation enhancer from thegroup consisting of: propylene glycol monolaurate, diethylene glycolmonoethyl ether, an oleoyl macrogolglyceride, a caprylocaproylmacrogolglyceride, and an oleyl alcohol; and delivering the selectedcannabinoid and permeation enhancer transdermally to treat an illness.2. The method of claim 1, wherein the delivering step comprises:providing an occlusive body having the selected cannabinoid andpermeation enhancer; and positioning the occlusive body on a patient. 3.The method of claim 2, wherein the occlusive body comprises: animpermeable backing; a rate-controlling microporous membrane, saidbacking and membrane defining a cavity therebetween; the selectedcannabinoid disposed within the cavity; the selected permeation enhancerdisposed within the cavity; a viscous flowable gel confined between thebacking and the membrane within the cavity for immobilizing thecannabinoid and the permeation enhancer; and means for attaching thebody to skin, wherein the selected cannabinoid and permeation enhancerare released through the membrane to the skin.
 4. The method of claim 1,wherein the illness is selected from AIDS, cancer, Huntington's disease,arthritis, nervous-tissue inflammation, vascular inflammation,inflammatory bowel disease, and other inflammation-related conditions.5. The method of claim 1, wherein the subject is selected from the groupconsisting of patients experiencing a loss of appetite, patientsexperiencing chronic pain, patients experiencing spasticity, patientsexperiencing dystonia, and patients experiencing nausea and vomiting. 6.The method of claim 1, wherein the cannabinoid is a combination ofcannabinoids selected from the group consisting of: cannabinol,cannabidiol, nabilone, levonantradol, (−)-HU-210, (+)-HU-210,1]-hydroxy-Δ⁹-THC, Δ⁸-THC-11-oic acid, CP 55,940, and R(+)-WIN 55,212-2.7. The method of claim 1, wherein the permeation enhancer is acombination of permeation enhancers selected from the group consistingof: propylene glycol monolaurate, diethylene glycol monoethyl ether, anoleoyl macrogolglyceride, a caprylocaproyl macrogolglyceride, and anoleyl alcohol.
 8. The method of claim 1, wherein the cannabinoid iscannabidiol and the permeation enhancer is diethylene glycol monoethylether.
 9. The method of claim 1, wherein the selected cannabinoid isdelivered via a topical formulation.
 10. The method of claim 1, whereinthe selected cannabinoid and permeation enhancer are delivered via apatch.
 11. The method of claim 1, further comprising the steps of:selecting an opiate; and delivering the selected opiate transdermallywith the selected cannabinoid and permeation enhancer.
 12. An occlusivebody for the delivery of cannabinoids, comprising: an impermeablebacking; a rate-controlling microporous membrane, said backing andmembrane defining a cavity therebetween; a cannabinoid disposed withinthe cavity; a permeation enhancer disposed within the cavity; and aviscous flowable gel confined between the backing and the membranewithin the cavity for immobilizing the cannabinoid and the permeationenhancer.
 13. The occlusive body of claim 12, wherein the cannabinoid isselected from the group consisting of: Δ⁹-THC, Δ⁸-THC, cannabinol,cannabidiol, nabilone, levonantradol, (−)-HU-210, (+)-HU-210,11-hydroxy-Δ⁹-THC, Δ⁸-THC-11-oic acid, CP 55,940, R(+)-WIN 55,212-2, orany combination thereof.
 14. The occlusive body of claim 12, wherein thepermeation enhancer is selected from the group consisting of: propyleneglycol monolaurate, diethylene glycol monoethyl ether, an oleoylmacrogolglyceride, a caprylocaproyl macrogolglyceride, and an oleylalcohol.
 15. The occlusive body of claim 12, further comprising anadhesive for attaching the occlusive body to a patient's skin andwherein the cannabinoid and permeation enhancer are released through themembrane to the patient's skin.
 16. The occlusive body of claim 12,wherein the occlusive body is a patch.
 17. The occlusive body of claim12, wherein the membrane has an exterior surface coated with anadhesive.
 18. The occlusive body of claim 17, wherein the adhesive is asilicone-based adhesive.
 19. The occlusive body of claim 12, wherein themembrane is hydrophobic and the cavity includes a hydrophilic wettingagent.
 20. The occlusive body of claim 12, wherein the cavity includeswater and a surfactant selected from a viscosity modifier and a gellingagent.
 21. The occlusive body of claim 20, wherein the surfactantcomprises methyl cellulose.
 22. The occlusive body of claim 12, furthercomprising an opiate confined in the cavity with the cannabinoid andpermeation enhancer.
 23. A method for increasing the concentration ofcannabinoids or cannabinoid metabolites in a subject, comprising:contacting the subject's skin with a compound selected from the groupconsisting of: cannabinol, cannabidiol, nabilone, levonantradol,(−)-HU-210, (+)-HU-210, 11-hydroxy-Δ⁹-THC, Δ⁸-THC-11-oic acid, CP55,940, and R(+)-WIN 55,212-2; and contacting the subject's skin with apermeation enhancer selected from the group consisting of: propyleneglycol monolaurate, diethylene glycol monoethyl ether, an oleoylmacrogolglyceride, a caprylocaproyl macrogolglyceride, and an oleylalcohol.
 24. The method of claim 23, further comprising contacting thesubject's skin with a drug metabolism inhibitor.
 25. The method of claim23, wherein the compound is a combination of compounds selected from thegroup consisting of: cannabinol, cannabidiol, nabilone, levonantradol,(−)-HU-210, (+)-HU-210, 1]-hydroxy-Δ⁹-THC, Δ⁸-THC-11-oic acid, CP55,940, and R(+)-WIN 55,212-2.